HIV-associated neurocognitive disorder (HAND) is a multifactorial disease with inflammation and immune activation as prominent features that remain post-HAART. There is a critical need to identify key host factors and understand their molecular mechanisms of action contributing to HAND. Macrophages play a central role in the development of HAND. Our long-term goals are to identify key cellular pathways at the immune/CNS axis that modulate HIV-macrophage interactions which negatively impact neuronal function leading to the development of HAND. Osteopontin (OPN) is a multifunctional cytokine-like, secreted glycophosphoprotein whose over-expression in brain, cerebral spinal fluid (CSF) and plasma, is associated with neurodegenerative diseases including in non-human primate models of HIV. However, no direct link of OPN to neuronal degeneration in HAND has yet been established. We identified OPN as an upregulated gene in HIV-infected macrophages. Knockdown of OPN in macrophages significantly decreases HIV replication suggesting the novel finding that OPN plays a positive role in the viral life cycle. Similar to another study, we found significantly elevated OPN levels n the CSF of HIV-infected persons with severe cognitive disorder compared to CSF from mildly demented and HIV negative control subjects. OPN was also significantly increased in brain tissue extracts from HIV-infected patients with cognitive disorder compared to unimpaired subjects. We believe that OPN, through its ability to increase monocyte recruitment into the CNS and to stimulate specific cytokine/chemokine and inflammatory pathways, plays a central role in the development of HAND. Importantly, these OPN-mediated pathways could provide new potential therapeutic targets. Our central hypothesis is that over-expression of OPN from macrophages is a host response to HIV infection that acts as a feedback loop stimulating further macrophage activation that triggers processes leading to neuronal injury and dysfunction. Two aims will test and examine this hypothesis: 1) To determine whether OPN expression is associated with neuronal degeneration in HAND and 2) To identify the molecular mechanisms by which OPN modulates HIV-1 replication.